Bicycloalkyl piperazine derivatives and process



United States Patent 3,309,370 BICYCLOALKYL PIPERAZINE DERIVATIVES ANDPROCESS Robert Norman Schut, Edward'sburg, Mich, assignor to MilesLaboratories, Inc., Elkhart, Ind., a corporation of Indiana No Drawing.Filed July 16, 1964, Ser. No. 383,239 11 Claims. (Cl. 260268) Thisinvention relates to bicycloalkanones. In one of its more particularaspects this invention relates to bicycloalkanone derivatives havingpharmacological activity.

The compounds of this invention constitute a series of piperazylsubstituted bicycloalkanones which can be represented by means of thestructural formula:

in which R is a hydrogen atom or an aryl radical, R is a hydrogen atomor an alkyl radical, R is a hydrogen atom, a halogen atom, or ahaloalkyl radical and X is a polycarbon lower alkylene radical.

The above structural formula shows the compounds of this invention inthe form of their free bases. How- .ever, these compounds can beprovided in the form of any ofa number of salts. For example, thecompounds can be prepared in the form of their hydrochlorides,hydrobromides, maleates, oxalates and other pharmacologically acceptablesalts. In general the free bases can be reacted with any acid, inorganicor organic, which will enter into salt formation with these bases.

The compounds of this invention can be prepared by reacting theappropriate phenyl substituted piperazine enamine of a cycloalkanonewith an a,/8-unsaturated aldehyde in a suitable solvent such as benzene.No catalyst is ordinarily required. The enamine can be readily preparedby reacting the appropriate cycloalkanone with the desired phenylsubstituted piperazine preferably in a suitable solvent such as tolueneand in the presence of an acid catalyst such as p-toluenesulfonic acid.The reaction is usually conducted at reflux in order to liberate water.The reactions involved in the preparation of the novel bicycloalkanonesof this invention can be illustrated by means of the following reactionsequence in which the various substituents are as above defined.

Acid

The reaction of phenyl substituted piperazine enamines with0a,,B-lll18flilll2lt6d aldehydes and aromatic ketones leads to novelaminopyran derivatives of the general formula:

wherein R R R and X are as above defined and R is a hydrogen atom or anaryl radical.

Where R is a hydrogen atom, that is, where the unsaturated carbonylcompound is a a,,8-unsaturated aldehyde, heating the aminopyranderivative in a mixture of triethylamine and dimethylformamide resultsin rearrangement to the corresponding bicycloalkanone as shown in thefollowing reaction sequence:

(III) X a sN-DMF Where R is an aryl radical, for example phenyl, theaminopyran derivative undergoes a retrocondensation in the presence of apolar solvent to produce an alkylated enamine derivative but does notundergo an internal Mannich reaction to produce the bicycloalkanone.Thus, in the case where R is aryl the aminopyran derivative reacts asfollows:

wherein the dotted lines signify that the position of the double bond isnot known with certainty.

This novel open-chain ketone is a useful chemical intermediate.

The novel bicycloalkanones of this invention have been shown to haveactivity as anti-inflammatory and analgetic agents.

This invention will be better understood by reference to the followingexamples which are included for the purpose of illustration and are notto be considered as limiting the scope of this invention which isdefined in the claims appended hereto. All temperatures given are indegrees centigrade unless otherwise noted.

EXAMPLE I 2- (4PHENYL-l-PIPERAZYL) -9 OXOBI CYCLO [3.3.1]NONANE A.1-(4-phenyl-1-piperazyl) cyclohexene A solution of 162 g. (1.0 mole) ofl-phenylpiperazine. 98 g. (1.0 mole) of cyclohexanone and 1 g. ofp-toluenc sulfonic acid in 300 ml. of toluene was heated under refluxfor 1 day. The water liberated was collected in a Dean-Stark trap. Thesolvent was distilled and the residue was-distilled in vacuo, B.P. -140(0.2 mm.) and recrystallized from 2-propanol, M.P. ll2-l 14, yield 84%vAnalysis.-Calcd. for C H N Found: N (basic), 5.92.

To a stirred solution of 14.1 g. (0.0583 mole) of 1-(4-phenyl-l-piperazyl)cyclohexene in 50 ml. of dry benzene was added asolution of 4.5 g. (0.080 mole) of acrolein (dried over MgSO in 25 ml.of dry benzene over a 30 minute period (5-10). The solution was stirredat this temperature for 1 hour, allowed to stand at room temperature for5 hours, then stored overnight in the refrigerator. Some white crystalshad formed by morning. These were collected, washed with a small amountof benzene ether, then dried (4.6 g.), M.P. 117118;

1 5 ,9 1660( -o-o=o), 1235,

1150 and 1070 cm. (ether) The n. rn.r. spectrum (CDCl showed resonancepeaks due to the 2 and 3 protons at 3.87 T (doublet) and 5.41 T(multiplet) respectively.

Analysis.-Calcd. for C H N O: C, 76.51; H, 8.72; N (total), 9.40; N(basic), 4.70. Found: C, 76.34; H, 8.66; N (total), 9.49; N (basic),4.69. The benzeneether filtrate from above was concentrated in vacuo togive a white solid. This material Was broken up, stirred with Skelly A(n-pentane), collected and recrystallized from benzene-Skelly B(n-hexane) to give 7.6 g. of white crystals, M.P. 1l3-114, undepressedwhen mixed with an analytical sample of the aminopyran. The total yieldwas 12.2 g. (71%).

C. 2-(4-phenyl-1-piperazyl)-9-0xabicycl0[3.3.1]n0nane* To a solution of9.03 g. of aminopyran in 100 ml. of freshly distilled dimethylformamidewas added 3.1 g. of triethylamine. The solution was heated in a nitrogenatmosphere for 12 hours at 7075. The solvents were removed bydistillation in vacuo and the residue was stirred with Skelly B. Thecrude solid weighed 7.61 g., M.P. 100105;

N (basic), 5.79.

1 5 3,9 1715 cut- Recrystallization from Skelly B and a few drops ofbenzene followed by recrystallization from a small quantity of methanolproduced the analytical sample, M.P. 129 131.

Analysis.Calcd. for C H N O: C, 76.51; H, 8.72; N, 9.40. Found: C,76.26; H, 8.45; N, 9.61.

D. 2-(4-phenyl-1-piperazyl)-9-0x0bicycl0[3.3.1]n0nane hydrochloride A10.0 g. sample of the free base was suspended in 2-propanol and treatedwith a slight excess of 1 moleequivalent of 3.4 N HCl-i-PrOH. Themixture was heated and the salt dissolved by addition of the minimalamount of water. Analytically pure monohydrochloride was isolated (6.0g.), M.P. 184185.

Analysis.Calcd. for C H N O'HCl: Cl, 10.59; N, 8.38. Found: Cl, 10.47;N, 8.26.

EXAMPLE II 2- 4-PHENYL1-PIPERAZYL) -3-METHYL-9-OXOBICYCLO [3.3.1] NONANEA. 8a-(4-phenyl-1-piperazyl)-3-methyl-4a,5,6,7,8,8a-

hexalzydr0 4H -benzopyran To a solution of 48.4 g. (0.20 mole) of1-(4-phenyl-1- piperazyl) cyclohexene dissolved in a minimal amount ofdry benzene was added a solution of 17.5 g. (0.25 mole) of methacroleinin 25 ml. of benzene. After being stored in the refrigerator for 5 days,the crystalline product was collected and washed with Skelly-benzene,yield 27.0 g. (43%) M.P. 121123. A sample was recrystallized from SkellyA-benzene (n-pentane-benzene) in the form of fluffy crystals, M.P.126-127,

911913 1680 111. 1210, 1165 and 1130 (s) Cmf 4 Analysis.-Calcd. for C HN O: C, 76.92; H, 8.97; N, 8.97. Found: C, 76.47; H, 8.84; N, 9.08.

B. 2-(4-phenyl-1-piperazyl) -3-methyl-9-0-x0bicycl0[3.3.1]n0nane (1)Isolation from bicyclic amin0ket0ne-amin0pyran mixture.-In a typical0.36 mole run, there was obtained 32.2 g. of aminopyran. The filtrate ondilution with Skelly A produced 25.0 g. of crude solid (bicyclicaminoketone). This material was dissolved in dilute hydrochloric acidand shaken with ether in order to remove neutral material. The aqueouslayer was basified and extracted with chloroform. The dried extract wasconcentrated in vacuo and the residue was purified by warming inmethanol, yield 6.38 g., M.P. 144145. The analytical sample was preparedby recrystallization from Skelly A-benzene, M.P. l45146;

011013 u 1705 cm. 1

Analysis.Calcd. for C H N O: C, 76.92; H, 8.97; N, 8.97. Found: C,76.37; H, 8.82; N, 9.28.

(2) IsOmerization of aminopyran (A) to bicyclic aminokezone (B).Asolution of 14.0 g. of the aminopyran in 200 ml. of purifieddimethylformamide and 25 ml. of triethylamine was heated under anitrogen atmosphere at 90 for 2 days. The solvents were concentrated invacuo and the residue dissolved in dilute hydrochloric acid. The freebase was isolated as described above for the aminopyran, yield 1.2 g.(9%), M.P. 144146.

C. 2-(4-phenyl-1-piperazyl)-3-methyl-9-0x0bicycl0[3 .3 .1 nommehydrobromide A 9.30 g. sample of the free base was dissolved in ml. ofethyl acetate and treated with 9.58 ml. of 3.11 NHBriPrOH. Theprecipitated salt was collected, washed with ethyl acetate and dried,yield 8.4 g. Recrystallization from i-P-rOHH O gave 4.70 g. of product,M.P. 179180 (dec.),

v52 1715 cm.-

Analysis.Calcd. for C H N O-HBr: Br, 20.33; N, 7.12. Found: Br, 20.72;N, 7.23.

EXAMPLE III 2 l-PHENYL-l-PIPERAZYL) -7-CYCLOHEXYL-9- iOXOBICYCDO[3.3.l]NONANE A. 1-(4-phenyl-1-piperazyl) -4-cyclo'hexylcyclohexene Thisenamine was prepared according to the procedure of Example IA using4-cyclohexylcyclohexanone as the cycloalkanone. The product was isolatedin a yield of 80%, M.P. 177- 179.

Analysis.-Calcd. for C H N N, 8.67. Found: N, 8.73.

B. 8a-(4-phenyl-Z-piperazyl)-6-cyclohexyl-4a,5,6,7,8,8ahexahydro -4HI-benzopyran To a stirred suspension of 64.8 g. (0.20 mole) of 1-(4-phenyl-l-piperazyl)-4-cyclohexylcyclohexene in ml. of dry benzene and150 ml. of dimethylformamide at 10 was added a solution of 13 g. ofacrolein in 50 ml. of benzene. The mixture was swirled on the steam bathuntil all the solid material had dissolved. The solution was stirred for30 minutes, allowed to stand at room temperature for 3 hours, thenstored in the refrigerator overnight. The solid which had precipitatedwas collected and washed wit-h Skelly A, yield 36.5 g., M.P. 108-110(cloudy melt). Concentration of the filtrate and stirring with Skelly Aproduced an additional 17.2 g. of product, M.P. 102106, total yield 53.7g. (71%). The analytical sample was prepared by recrystallization frombenzene- Skelly B, M.P. 107-109;

V33? 1660 (111.) cm."

Analysis.Calcd. for C H N O: C, 78.95; H, 9.47; N, 7.37. Found: C,78.58; H, 9.36; N, 7.47.

C. 2-(4-phenyl-I-piperozyl)-7-cyclohexyl-9-oxabicyclo [3.3.1]-nnane Asolution of 53.7 g. (0.14 mole) of aminopyran in 600 ml. ofdimethylformamide and 60 ml. of triethylamine was heated at 7580 for 40hours under a nitrogen atmosphere. Concentration in vacuo gave an orangecolored sirup. Stirring in Skelly A gave a greasy solid which wasdissolved in benzene. Addition of excess dilute hydrochloric acidresulted in the formation of a crude hydrochloride. The acid filtratewas made basic and extracted with chloroform. Drying and concentrationin vacuo gave an oil from which it was possible to obtain 2.0 g. ofsolid material by chilling in methanol; M.P. 135138;

The crude hydrochloride mentioned above was also converted to the freebase, yield 13.3 g., M.P. 124-125,

A 5.61 g. sample of the free base dissolved in warm 2-propanol-ether wastreated with 5.22 ml. of 2.84 NHCliPrOH. On cooling a crystalline whitesalt formed, yield 4.6. g. Recrystallization from isopropyl alcohol gave2.50 g. of purified product, M.P. 175176 (dec.),

I 1155,, 1720 cm."

Analysis.-Calcd. for C H N O-HCh Cl, 8.51; N,

6.71. Found; Cl, 8.44; N, 6.71.

1 EXAMPLE I A. 1-(4-phenyl-1-piperazyl)cyclopentene This enamine wasprepared according to the procedure of Example IA using cyclopentanoneas the cycloalkanone. The product was isolated in a yield of 61%, M.P.101.

Analysis-Calcd. for C H N z N, 12.27. Found: N,

B. 2-(4-ph enyl-1-pipgrlzzyl)-8-oxobicyclo [3.2.1]0ctane Acrolein (ca.0.25 mole) was added to a stirred solution of1-(4-phenyl-1-piperazyl)cyclopentene in dry benzene. The temperature wasmaintained below 20 by means of an ice-bath. After standing in therefrigerator overnight, the solvent was distilled in vacuo. The lightsirup was stirred in Skelly A to gradually give a greasy solid. Stirringthis material with warm ether produced a light tan solid, yield 20.7 g.(37%), M.P. 128-131;

For further purification, the product was dissolved in dilutehydrochloric acid and the solution shaken with ether to remove neutralmaterial. Regeneration of the free base and recrystallization frommethanol give the bicyclic aminoketone as fine needles, M.P. l37138.

Analysis.Calcd. -for C H N O: C, 76.06; H, 8.45; N, 9.86. Found: C,75.88; H, 8.78; N, 10.07.

C. 2-(4-phenyl-I -p iperazyl)-8-0x0bicycl0 [3 .2 .1 ]0ctanehydrochloride hydrate A 23.6 g. sample (0.0831 mole) of the free base in100 ml. of isopropyl alcohol and 250 ml. of warm ethyl acetate wastreated with 29.3 ml. of 2.84 N

6 HCliPrOH (1 mole-equiv.). The precipitated salt was recrystallizedfrom aqueous isopropyl alcohol, yield 14.5 g., M.P. 196197 (dec.) withdroplets of moisture appearing in the top portion of the tube during themeasurement. The analysis indicated a hydrate and the infrared spectrum(KCl) showed only a very weak band in the 1750 cm. region in agreementwith carbonyl hydration.

Analysis.Calcd..for C H N O-HCl-H O: Cl, 10.47; N, 8.26. Found: Cl,10.42; N, 8.45.

D. 2-(4-phenyl-1-piperazyl)-8-0x0bicyclo[3.2.1]octane hydrochloride Asample of the hydrate was heated for 10 hours in the Abderhalden pistolat -112 (in vacuo). The anhydrous product had M.P. 196197 (dec.). Theinfrared spectrum (KCl) now showed a strong band at 1755 cm.-

Analysis.-Calcd. for C H N O-HC1: Cl, 11.05; N, 8.72. Found: Cl, 11.01;N, 8.92.

EXAMPLE V A. 1-(4-phenyl-1-piperazyl)cycl0heptene This enamine wasprepared according to the procedure of Example IA using cycloheptanoneas the cycloalkanone. The product was isolated in a yield of 27%, M.P.59-61.

Analysis.Calcd. for C H N N, 10.92. Found: N, 11.09.

B. 2-(4-phenyl-1-piperazyl)-10-0x0bicycl0[3.4.1]decane C.2-(4-phenyl-1-piperazyl)-10-0x0bicycl0[3.4.1]decane hydrobromide To thefree base (6.0 g.) in methanol was added excess hydrogen bromide in2-propanol. The salt was dissolved by the addition of just the requiredamount of water to the boiling alcohol suspension. The white crystalswhich formed amounted to 4.2 g., M.P. 226- 227.

Analysis. Calcd. for c H N O-HBr; Br, 20.32. Found: Br, 20.48.

EXAMPLE VI a A. 2-(4-phcnyl-1-piperazyl)-4-phenyl-9-oxobicycl0[3.3.1]-n0nane The free base was prepared in benzene solution startingwith 1-(4-phenyl-1-piperazyl)cyclohexene and cinnamaldehyde. Afterremoval of solvent the residue was stirred with Skelly A to give asolid. Recrystallization from benzene-Skelly A gave the bicyclicaminoketone in 36% yield, M.P. 167-168;

Analysis.-Calcd. for C H N O: N (basic), 3.74. Found: N (basic), 3.72.

B. 2-(4-phenyl-1-piperazyl)-4-phenyl-9-0x0bicyclo [3.3.1]-n0nanehydrochloride The salt was prepared in the usual manner from hydrogenchloride-isopropyl alcohol; M.P. 229-230.

Analysis. Calcd. for C H N O-HCl: Cl, 8.65. Found: Cl, 8.48.

7 EXAMPLE VII 2-(4-n1-CHLOROPHENY'L-1-PIPERAZYL-9OXOBI- 'CYCLO[3.3.1]1NONANE A. 1-(4-m-chl0r0phenyl-1-piperdzyl) cyclohexene' Thisenamine was prepared according to the procedure of Example IA using1-m-chlorophenylpiperazine as the piperazine derivative. The product wasisolated in a yield of 100%, B.P. 160170 (0.15 mm.).

Analysis.Calcd. for C H ClN N (basic), 5.06. Found: N (basic). 5.01.

B. 8a- (4-m-chlorophenyl-1 -piperazyl -4a,5,6,7,8ahexahydr-4H-1-benz0pyran This intermediate was prepared according to the proceduredescribed for the previously mentioned aminopyrans using1-(4-m-chlorophenyl-1-piperazyl)cyclohexene and acrolein. The materialwas isolated as an ivory colored solid in 85% yield, M.P. 8892.Recrystallization from ether-isopropyl alcohol gave purified product,M.P. 94.5 96;

155,9 1660 Ont- Analysin-Calcd. for C H ClN O: N (basic), 4.21. Found: N(basic), 4.26.

A 25.9 g. sample of the aminopyran in 500 ml. of distilleddimethyl'formamide and 50 ml. of triethylamine was heater under anitrogen atmosphere at 80-90 :for 1 day. The solvents were removed invacuo and the residue treated with dilute hydrochloric acid. The neutralmaterial was removed by extraction with ether and the free base wasregenerated. A chloroform extract yielded 21.2 g. of basic sirupymaterial. This crude product crystallized when stirred with coldmethanol, yield 11.0 g., M.P. 8891. Recrystallization from methanolcontaining a small amount of ether gave crystals of M.P. 9496";

vCHCh 1710 cm." (6.6 g.)

max. Analysis.-Calcd. for C H ClN O: N (basic), 4.21. Found: N (basic),4.27.

D. 2-(4-m-chl0rophenyl-I-piperazyl)-9-0x0bicyclo [3.3.1]n0nanehydrochloride The hydrochloride was prepared in HCl-iPrOH from 6.17 g.of the free base (M.P. 9496); yield of salt, 6.25 g., M.P. 193194(dec.). Recrystallization from aqueous isopropyl alcohol gave 2.65 g. ofanalytically pure product, M.P. l95196 (dec.).

Analysis.Calcd. for C H ClN O-CHh Cl, 9.59; N, 7.75. Found: Cl, 9.53; N,7.48.

EXAMPLE VIII A. 2,4-diphenyl-8a-(4-phenyl-1-piperazyl)-4a,5,6,7,8,8ahexahydr0-4H-1 -benz0pyran A solution of 52.0 g. (0.25mole) of chalcone in benzene was added to a stirred solution of 60.5 g.(0.25 mole) of 1 (4 phenyl 1-piperazyl)-cyclohexene in benzene. Afterstanding for 3 days, the benzene was removed in vacuo and the residualsirup was stirred with Skelly A. The solid material which formed wascollected and washed with Skelly A, yield 48.5 g. (44%), M.P. 115-117,

.ggQ 1660 mm (medium) Two crystallizations from benzene-Skelly A gavethe analytical sample, M.P. 129.5130.5.

Analysis.Calcd. for C3 H N O: C, 82.66; H, 7.56; N, 6.22. Found: C,82.47; H, 7.34; N, 6.23.

B. 1-(4-1ihenyl-1-piperazyl)-2(6)-(1-phenyl-2-benz0ylethyl)-cyclohexeneIn a 0.27 mole run carried out as described above the residual sirupobtained on concentration of the reaction solution was crystallized frommethanol instead of Skelly A, yield 60%, M.P. 135-136,

V 1685, 1645 (W.) cm.*

EXAMPLE IX 2-phenyl-8a-(4-phenyl-1-piperazyl)-4a,5,6,7,8,8ahexahydro-4H-1-benzopyran The reaction was carried outaccording to the procedure of Example VIIIA using 0.05 mole quantitiesof acrylophenone and 1-(4-phenyl-1-piperazyl)cyclohexene. The yield ofcrude product was 75%, M.P. 87-91. Recrystallization from SkellyA-benzene and a further recrystallization from Skelly B gave theanalytical sample, M.P. 9697 Analysis.Calcd. for C H N 0: N, 7.49.Found: N, 7.40.

EXAMPLE X A. 1-(m-trifluoromethylphenyl)-4-(1-cycl0hexenyl) piperazineThis enamine was prepared according to the procedure of Example IA using1-m-trifiuoromethylphenylpiperazine as the piperazine derivative. Theproduct was isolated in a yield of 69%, B.P. 154169 (0.15 mm.).

Analysis.Calcd. for C H F N- N (basic), 4.51. Found: N (basic), 4.53.

B. 2- (4-m-triflu'oromethylphenyl-1-piperazyl) -9-oxobicyclo-[3.3.1]n0nane To a stirred solution of 46.5 g. (0.145 mole)of l-(mtrifluoromethylphenyl)-4-(1 cyclohexenyl)piperazine in 250 ml. ofdry benzene was added 11.4 g. (0.20 mole) of acrolein in 25 ml. of drybenzene. The solution was stirred at 10-15 for 30 minutes and thenallowed to stand at room temperature 1 hour. After storing 12 hours inthe refrigerator, the solvent was removed in vacuo and the residuedissolved in 500 ml. of dimethylformamide and 50 ml. of triethylamine.The solution was heated in.

a nitrogen atmosphere for 16 hours at 90. The solvent was removed andthe residue dissolved in ether. The solution was shaken with dilutehydrochloric acid. The aqueous layer was separated, made alkaline withsodium hydroxide solution, and extracted with chloroform. The extractwas dried and concentrated in vacuo. Distillation of the residue gave 21g. of material, B.P. 200- 210 (0.25 mm.). Crystallization from Skelly Bgave 6.5 g. of low melting solid.

Analysis.-Calcd. for C H F N N (basic), 3.82. Found: N (basic), 3.84.

C. 2-(4-m-trifluoromethy[phenyl-1-piperazyl)-9-0x0- bicyclo- [3.3.1]n0nane hydrochloride A solution of HCl in 2-propanol (1mole-equiv.) was added to 6.0 g. of the free base. The salt wascollected and dried, yield 4.0 g., M.P. 209-210.

Analysis.-Calc-d. for C H F N -HC1: Cl, 8.80; N, 6.96. Found: Cl, 8.75;N, 7.00.

The various compounds described in the above examples are shown in TableI with their physical and chemical characteristics.

In summary this invention relates to a series of novel piperazylsubstituted bicyc'loalkanones which have useful pharmacological activityto intermediate aminopyran derivatives prepared in the synthesis thereofand to openchain ketones prepared from such :a-minopyran derivatives.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformula wherein R is a member selected from the group consisting ofhydrogen and phenyl, R is a member selected from the group consisting ofhydrogen and methyl, R is a member selected from the group consisting ofhydrogen, halogen and trifluoromethyl and X is a member selected fromthe group consisting of lower alkylene and cyclohexyl lower alkylene andsalts of said compounds with pharmacologically acceptable anions.

2. 2 (4 phenyl l-piperazyl)-9-oxobicyclo[3.3.l]

nonane.

3. 2 (4 phenyl-l-piperazyl)-3-rnethyl-9-oxobicyclo [3.3.1]nonane.

4. 2 (4 phenyl l-piperazyl)-7-cyclohexyl-9-oxobicyclo[3.3.1]nonane.

5. 2 (4 phenyl l-piperazyl)-8-0Xobicyclo[3.2.1] octane.

6. 2 (4 phenyl-l-piperazyl)--oxobicyclo[3.4.1]decane.

7. 2 (4 phenyl-l-piperazyl)-3-phenyl-9-oxobicyclo [3.3.1]nonane.

8. 2 (4 m chlorophenyl-l-piperazyl)-9-oxobicyclo [3.3.1]nonane.

9. 2 (4 m trifluoromethylphenyl-1-piperazyl)-9- oxobicyclo [3 .3 lnonane.

10. A process for the preparation of a compound of the formula wherein Ris hydrogen, R is a member selected from the group consisting ofhydrogen and methyl, R is a member selected from the group consisting ofhydrogen, halogen and trifluoromethyl and X is a member selected fromthe group consisting of which comprises heating a compound of theformula wherein R R R and X are as above defined, with 24 triethylamineand dimethylformamide to produce a compound of the formula wherein R R Rand X are as above defined. 11. A process for the preparation of acompound of the formula which comprises reacting a compound of theformula wherein R and X are as above defined, with a compound of theformula o EIC=C -13:

a i wherein R and R are as above defined in a nonpolar solvent at roomtemperature, to produce an isolatable crystalline intermediate of theformula wherein R R R and X are as above defined, and heating saidintermediate with triethylamine and dimethylformamide to produce acompound of the formula wherein R R R and X are as above defined.

References Cited by the Examiner UNITED STATES PATENTS 10/1963 Poos260-268 OTHER REFERENCES Lebel et al.: Tetrahedron, vol. 20, pp.215-229, February 1964.

Stork et al.: Journ. Amer. Chem. Soc., vol. 78, pp. 5129-30, 1956.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

I. W. ADAMS, JR., Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,309,370 March 14, 1967 Robert Norman Schut It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 2, line 18, for N-DMF" read Et NDMF column 3, line 13, for"benzene ether" read benzene-ether column 4, line 55, for "4H" read 4H-lines 72 and 73, for

CHCl 1 CHClg l v 1660 (m.) cm. read v 1660 (m.) cm.

max max column 5, line 66, for "give" read gave column 7, line 9, for"170" read 170 line 12, after "7," insert 8, line 30, for "heater" readheated line 51, for "CH1" read HCl columns 9 and 10, TABLE I, ExampleI-B,

for that portion of the structure reading read columns 11 and 12,Example III-B, for "78-95" read 78.95 columns 15 and 16, Example V-B,for that portion of the structure reading read n u sla7meanEdxalngple VB for C H N O read C H N O columns Example VI-B, for that portion of thestructure reading Example VII-B, for "C H CIN O" read C H ClN- O columns19 and 20, Example VII-C, for "C H ClN O" read C H ClN O Example VII-D,for "c H c1N 0-Hc1" read H ClN O-HCl Example VIII-A, for "C H N O" readC H N O column 23 line 3, after "activity" insert a comma;

same column 23, lines 66 to 71, for that portion of the structurereading read N, 91

column 24, line 18, strike out "the group consisting of".

Signed and sealed this 25th day of June 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissionerof Patents

1. COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA
 11. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA